An Atypical Presentation of Primary Hyperparathyroidism in an Adolescent: A Case Report of Hypercalcaemia and Neuropsychiatric Symptoms Due to a Mediastinal Parathyroid Adenoma.

Psychiatric disorders are rare clinical manifestations of hypercalcaemia in the pediatric population, are relatively more frequent during adolescence and are often overlooked in cases of severe hypercalcaemia. We described the case of a 17-year-old girl affected by anorexia nervosa, depression and self-harm with incidental detection of moderate hypercalcaemia. Clinical, laboratory and instrumental tests demonstrated that hypercalcaemia was secondary to primary hyperparathyroidism (PHPT) due to a mediastinal parathyroid adenoma in the thymic parenchyma. After parathyroidectomy with robot-assisted surgery, we observed the restoration of calcium and PTH levels in addition to an improvement in psychiatric symptoms. This case demonstrates that serum calcium concentration should be evaluated in adolescents with neurobehavioural symptoms and in cases of hypercalcaemia PHPT should be excluded. Surgery represents the cornerstone of the management of PHPT and may contribute to improving quality of life and psychological function in these patients. However, the complexity of neurological involvement in cases of hypercalcaemia due to PHPT requires further investigations to establish the real impact of this condition on the neurocognitive sphere.

Case report of a familial triple: a syndrome and review of the literature.

RATIONALE: Triple-A syndrome, or Allgrove syndrome (AS), is a rare autosomal recessive disorder characterized by the alacrimia, achalasia, and adrenal insufficiency triad. Alacrimia usually starts at early infancy, while achalasia and adrenal insufficiency appear later during childhood or adulthood. Some patients may also present with the so-called Double-A syndrome (i.e., alacrimia and achalasia, or alacrimia and adrenal insufficiency); adrenal insufficiency usually represents a life-threatening event due to severe hypoglycemia. Many patients may also present other associated manifestations, such as neurological disorders. We describe, here, 2 sisters of non-consanguineous parents. PATIENT CONCERNS: An 8-year-old girl was admitted to the Pediatric Care Unit of Parma after an episode characterized by seizure with loss of consciousness and generalized hypertonia lasting a few minutes. Her sister, a 6-year-old girl, presented with recurrent episodes of vomiting and failure to thrive. DIAGNOSES: Both children were investigated by laboratory tests, esophagogastroduodenoscopy, and imaging. The first patient had the complete triad of AS (alacrimia, achalasia, adrenal insufficiency), while the second one presented only alacrimia and achalasia. Both resulted from a mutation in the achalasia, addisonianism, alacrimia syndrome gene. INTERVENTIONS: Both patients were treated with oral hydrocortisone for Addison disease, and with artificial tears in the first case. After many pneumatic endoscopic dilations and therapy with nifedipine, both patients underwent surgical Heller myotomy for achalasia. OUTCOMES: A rapid and favorable recovery to normal diet and with improvement of growth parameters was obtained. These cases are also compared with the literature data, reported in a brief review. LESSONS: AS is a rare multisystemic disorder. The longer diagnosis is delayed, the greater extent to which this syndrome may be life-threatening, mainly because of hypoglycemia due to adrenal insufficiency. In AS, the red-flag symptom of alacrimia should instigate investigation for achalasia, Addison disease, and achalasia, addisonianism, alacrimia syndrome gene mutation.

Pediatric gastroenteropancreatic neuroendocrine tumor: A case report and review of the literature.

INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of epithelial neoplasms originating from the diffuse neuroendocrine cell system of the gastrointestinal tract and pancreas. They are very rare, especially in pediatric age, and vary widely in terms of clinical presentation, malignant potential, and prognosis. PATIENT CONCERNS: A 9 years' old, white female child presented with abdominal pain and diarrhea mixed with bright red blood lasting 2 days followed by hematemesis. DIAGNOSIS: Routine laboratory tests revealed microcytic anemia. Upper endoscopy showed a 20-mm polypoid lesion in the posterior wall of the duodenal bulb. Biopsy specimens were taken and histologic analysis showed a well-differentiated neuroendocrine tumor G1, with a ki-67 index <2%, an expression of chromogranine A (CgA), synaptophysin and somatostatin receptor type 2A (SSTR2A). Endoscopic ultrasound showed a 21-mm hypoechoic, hypervascular lesion involving the mucosal, submucosal, and muscular layers and a 15-mm hypoechoic round periduodenal lymph node. Gallium-68-somatostatin receptor positron emission tomography (PET with Ga-DOTATOC) showed one area of tracer uptake in the duodenum and other one near the duodenum compatible with the primary tumor site and a lymph node respectively. All the tests confirmed the diagnosis of a GEP-NET of the duodenal bulb, with a single lymph-node metastasis. INTERVENTIONS: The patient underwent an open duodenal wedge resection. OUTCOMES: The follow-up at 6, 24, and 36 months and then yearly after surgery for a total of 42 months showed no evidence of recurrence. CONCLUSION: Duodenal neuroendocrine tumors represent 1% to 3% of all GEP-NETs. They are rare in adults and extremely rare in children. Therefore, the diagnostic and therapeutic approach should be multidisciplinary, including laboratory, endoscopic, and specific imaging tests and strictly follows guidelines, to avoid misdiagnosis and inadequate treatments. Although the prognosis is benign in most cases, they can present with metastases. Therefore, a careful follow-up is extremely important.

Thyroid and celiac disease in pediatric age: a literature review.

Chronic autoimmune thyroid disease or Hashimoto thyroiditis (HT) and Graves-Basedow disease (GD) are the main autoimmune thyroid diseases in pediatric age. Both are characterized by the production of anti-thyroid antibodies, by an infiltration of autoreactive B and T lymphocytes into the thyroid parenchyma and by alterations in thyroid function (hyperthyroidism in GD, normal function or subclinical hypothyroidism in HT with possible evolution towards manifest hypothyroidism). Celiac disease (CD) is a systemic autoimmune disease caused by gluten ingestion in genetically predisposed subjects, its prevalence is around 1% in Western Countries. It presents with a pathognomonic enteropathy, a variety of clinical manifestations, positivity for specific antibodies, positivity for typical haplotypes HLA DQ2/DQ8. The clinical manifestations may vary among four types: typical, atypical, silent and latent. Diagnosis can be made in presence of specific histopathologic findings in duodenal biopsies and antibodies positivity. Celiac disease is associated to various endocrine autoimmunities such as thyropathies, diabetes mellitus type 1, Addison disease, multiendocrine syndromes. The most frequent associated thyropaties are HT and GD. The present review aims to explore the associations between thyropathies and celiac disease in pediatric age.

Renal lithiasis and inflammatory bowel diseases, an update on pediatric population.

BACKGROUND AND AIM OF THE WORK: Historical studies have demonstrated that the prevalence of symptomatic nephrolithiasis is higher in patients with inflammatory bowel disease (IBD), compared to general population. The aim of the review was to analyze literature data in order to identify the main risk conditions described in literature and the proposed treatment. METHODS: A research on the databases PubMed, Medline, Embase and Google Scholar was performed by using the keywords "renal calculi/lithiasis/stones" and "inflammatory bowel diseases". A research on textbooks of reference for Pediatric Nephrology was also performed, with focus on secondary forms of nephrolithiasis. RESULTS: Historical studies have demonstrated that the prevalence of symptomatic nephrolithiasis is higher in patients with inflammatory bowel disease (IBD), compared to general population, typically in patients who underwent extensive small bowel resection or in those with persistent severe small bowel inflammation. In IBD, kidney stones may arise from chronic inflammation, changes in intestinal absorption due to inflammation, surgery or intestinal malabsorption. Kidney stones are more closely associated with Crohn's Disease (CD) than Ulcerative Colitis (UC) in adult patients for multiple reasons: mainly for malabsorption, but in UC intestinal resection may be an additional risk. Nephrolithiasis is often under-diagnosed and might be a rare but noticeable extra-intestinal presentation of pediatric IBD. Secondary enteric hyperoxaluria the main risk factor of UL in IBD, this has been mainly studied in CD, whether in UC has not been completely explained. In the long course of CD recurrent urolithiasis and calcium-oxalate deposition may cause severe chronic interstitial nephritis and, as a consequence, chronic kidney disease. ESRD and systemic oxalosis often develop early, especially in those patients with multiple bowel resections. Even if we consider that many additional factors are present in IBD as hypomagnesuria, acidosis, hypocitraturia, and others, the secondary hyperoxaluria seems to finally have a central role. Some medications as parenteral vitamin D, long-term and high dose steroid treatment, sulfasalazine are reported as additional risk factors. Hydration status may also play an important role in this process. Intestinal surgery is a widely described independent risk factor. Patients with ileostomy post bowel resection may have relative dehydration from liquid stool, which, added to the acidic pH from bicarbonate loss, is responsible for this process. In this acidic pH, the urinary citrate level excretion reduces. The stones most commonly seen in these patients contain uric acid or are mixed. In addition, the risk of calcium containing stones also increases with ileostomy. The treatment of UL in IBD involves correction of the basic gastrointestinal tract inflammation, restricted dietary oxalate intake, and, at times, increased calcium intake. Citrate therapy that increases both urine pH and urinary citrate could also provide an additional therapeutic benefit. Finally, patients with IBD in a pediatric study had less urologic intervention for their calculosis compared with pediatric patients without IBD.

Inverse association between Helicobacter pylori and inflammatory bowel disease: myth or fact?

BACKGROUND: Inflammatory bowel diseases (IBD), are chronic, relapsing-remitting diseases of the gastrointestinal tract, including Crohn's disease (CD), Ulcerative colitis (UC) and Unclassified IBD (IBDU). Their pathogenesis involves genes and environment as cofactors in inducing autoimmunity; particularly the interactions between enteric pathogens and immunity is being studied. Helicobacter pylori (HP) is common pathogen causing gastric inflammation. Studies found an inverse prevalence association between HP and IBD, suggesting a potential protecting role of HP from IBD. METHODS: A literature search of the PubMed database was performed using the key words ''helicobacter pylori'', ''inflammatory bowel disease'', ''crohn disease'', "ulcerative colitis". Embase, Medline (OvidSP), Web of Science, Scopus, PubMed publisher, Cochrane and Google Scholar were also searched. Prevalence rate-ratios among HP in IBD patients, HP in CD patients, HP in UC patients, HP in IBDU patients were extracted, each group was compared with controls, to verify the inverse association between HP and IBD prevalence. RESULTS: In all groups the dispersion of data suggested an inverse association between IBD group and controls, even when the comparison was carried out separately between each group of newly diagnosed patients and controls, to rule out the possible bias of ongoing pharmacologic therapy. CONCLUSIONS: The results of this review show a striking inverse association between HP infection and the prevalence of IBD, independently from the type of IBD considered across distinct geographic regions. Anyway, data should be interpreted cautiously, as wider, prospective and more homogeneous research on this topic are awaited, which could open new scenarios about environmental etiology of IBD.

Eosinophilic esophagitis in pediatric age, state of the art and review of the literature.

Eosinophilic esophagitis (EoE) is a chronic immune-mediated relapsing disease caused by eosinophilic infiltration of the esophageal mucosa which is normally lacking these cells. EoE belongs to the group of the so called Eosinophilic Gastrointestinal Disorders (EGIDs). From a rare and unusual disease, EoE has become an emerging entity and in recent years its incidence and prevalence have increased all over the world, also in children. The pathogenesis is very complex and still not completely clear. Esophageal disfunction symptoms (e.g. dysphagia and food impaction) represent the typical manifestation of EoE and this condition could be difficult to recognize, more in pediatric age than in adults. Moreover, symptoms can often overlap with those of gastro-esophageal reflux disease (GERD), leading to a delayed diagnosis. EoE is often related to atopy and an allergological evaluation is recommended. Untreated EoE could provoke complications such as strictures, esophageal rings, narrowing of the esophagus. Diagnosis is confirmed by the demonstration in biopsy specimens obtained through upper endoscopy of eosinophilic inflammation (>15 for high powered field) of the esophageal mucosa and other histological features. Other tests could be useful not specifically for the diagnosis, but for the characterization of the subtype of EoE. Since EoE incidence and knowledge about physiopathology and natural history have increased, the goal of the review is to provide some helpful tools for the correct management in pediatric age together with an overview about epidemiology, pathogenesis, clinical, diagnosis and treatment of the disease.

How and when investigating and treating Helicobacter pylori infection in children.

For thousands of years humans have lived in symbiosis with Helicobacter pylori. This infection is acquired mainly during childhood and, despite it represents one of the most common infections in humans, only a minority of infected people may develop health issues and life-threatening diseases. For diagnosing Helicobacter pylori infection in children we can use, at first, non-invasive diagnostic tests, if clinical pattern and/or history are of suspicion. Then, invasive tests i.e. gastroscopy are necessary to confirm the infection. As antibiotics are not widely available in children affected by Helicobacter pylori infection, they should be chosen based on individual antibiotic susceptibility testing obtained by gastric biopsy specimens or the local antibiotic resistance pattern, in empirical treatment is chosen. Test and treat strategy in children should be avoided. In this brief review we summarize how and in which children the infection should be investigate and which the most appropriate eradication treatment should be chosen.

Risk of tumor implantation in percutaneous endoscopic gastrostomy in the upper aerodigestive tumors.

Percutaneous endoscopic gastrostomy (PEG) has become a mainstay in providing enteral access for patients with obstructive head, neck and esophageal tumors. Tumor cell implantation is a rare complication in patients with aerodigestive cancers, who have undergone PEG tube placement. The objective of this review is to determine the incidence and contributing risk factors leading to the implantation of metastases into the abdominal wall following PEG placement. A comprehensive review of the literature in PUBMED (2008-2018) was performed.  The literature search revealed reports of more than 50 cases of abdominal wall metastases after PEG placement. As most of these studies were case reports, the exact rate of metastasis remains unknown. Generally pharyngoesophageal location of primary cancer (100%), squamous cell histology (98%), poorly differentiated tumor cells (92%), advanced pathological stage (97%), and large primary cancer size were identified as strong risk factors for the development of stomal metastasis. Abdominal wall metastases following PEG placement are a rare but serious complication in patients with head and neck malignancy.

Serum CXCL10 levels and occurrence of thyroid dysfunction in patients treated with interferon-alpha therapy for hepatitis C virus-related hepatitis.

OBJECTIVE: Thyroid autoimmunity is a common side effect of interferon-alpha (IFN-alpha) treatment for chronic hepatitis C. There are currently no reliable parameters to predict the occurrence of thyroid dysfunctions in patients undergoing IFN-alpha therapy. CXC chemokine ligand 10 (CXCL10) is a chemokine known to play a role in both thyroid autoimmune disease and hepatitis C virus (HCV) hepatitis. DESIGN: The aim of this study was to evaluate serum CXCL10 levels in HCV patients treated with IFN-alpha in relation to the occurrence of thyroid dysfunctions. Serum CXCL10 levels were assayed in 25 HCV patients (proven to be negative for serum thyroid antibodies) before and during IFN-alpha therapy (2, 4 and 6 months) and in 50 healthy controls. HCV patients were retrospectively selected according to the occurrence of IFN-alpha-induced thyroid dysfunction and were assigned to two groups. Group I included 15 patients who did not develop thyroid antibody positivity or dysfunction; group II included ten patients who showed the appearance of serum thyroid antibodies, followed by clinically overt thyroid dysfunction. RESULTS: Patients with HCV, regardless of the development of thyroid dysfunctions, had significantly higher serum CXCL10 than controls (261.6+/-123.4 vs 80.4+/-33.6 pg/ml; P<0.00001). Pretreatment mean serum CXCL10 levels were significantly higher in Group I versus Group II (308.6+/-130.7 vs 191.1+/-69.4 pg/ml; P<0.05). Groups I and II showed different rates of favourable response to IFN-alpha treatment (33 and 90% respectively). CONCLUSION: Our results suggest that measuring serum CXCL10 before IFN-alpha treatment may be helpful for identifying those patients with higher risk to develop thyroid dysfunction, and require a careful thyroid surveillance throughout the treatment.

Graves' disease in interferon-alpha-treated and untreated patients with chronic hepatitis C virus infection.

An association between Graves' disease (GD) and chronic hepatitis C (C-HC) has been observed both in the presence and the absence of recombinant interferon-alpha (rIFN-alpha) treatment. rIFN-alpha-induced GD is characterized by suppressed thyroid-stimulating hormone levels; normal or elevated free triiodothyronine (FT3) and free thyroxine (FT4) values; the presence of thyroid peroxidase antibodies, antithyroglobulin antibodies, and thyroid receptor antibodies; and high iodine thyroid uptake. In contrast, GD developed during C-HC without rIFN-alpha is less clearly defined. In this study, we examined two groups of patients: group A, 28 patients with C-HC treated with rIFN-alpha who developed GD after 1 to 9 months, and group B, 10 patients with C-HC who developed GD without a previous rIFN-alpha treatment. At the time of GD, both groups started methimazole therapy; thyroid function was reevaluated after 3, 6, 9, and 12 months. Group A patients continued IFN. After 12 months, all patients of group A were euthyroid, and 21 of them (75%) had already stopped methimazole treatment, whereas all patients of group B were euthyroid and only 2 (20%) had stopped methimazole. In conclusion, the data show a better course of GD, with a more precocious and significantly higher number of recoveries in patients with rIFN-alpha-induced GD than in rIFN-alpha-unrelated disease. Further studies are needed to establish whether the two types of GD differ not only from a clinical point of view but also because of different underlying pathogenetic mechanisms.

Course of graves disease in interferon-treated patients with chronic hepatitis C virus infection and in uninfected patients.

BACKGROUND: The development of thyroid antibodies and the alteration of thyroid function are the most common disorders associated with interferon alfa therapy in individuals with chronic hepatitis C (CHC).In this study, we compared the course of Graves disease (GD) between patients diagnosed with CHC and treated with interferon alfa and uninfected patients. METHODS: We retrospectively analyzed data from 39 GD patients (15 men and 24 women, group 1) affected by CHC and treated with interferon alfa and from 43 uninfected GD patients (19 men and 24 women, group 2) who were seen at our institution from 1999 to 2011. All GD patients were treated with methimazole (MMI). Daily dose of MMI, duration of MMI therapy, and remission rate were evaluated in both groups. RESULTS: The daily dose of MMI was found to be lower in group 1 as compared with group 2 (9.74 ± 5.94 mg/d vs 14.12 ± 8.64 mg/d in group 1 vs group 2, respectively, P < 0.01). In addition, the duration of MMI treatment was found to be lower in group 1 as compared with group 2 (13.98 ± 13.0 months vs 38.86 ± 27.13 months in group 1 vs group 2, respectively; P < 0.01). The remission rate from GD was higher in the patients of group 1 in comparison with the patients of group 2 (87.17 % vs 48.86% in group 1 vs group 2, respectively, P < 0.005). CONCLUSION: Altogether, our data demonstrate a more favorable course of GD in the patients with CHC treated with interferon alfa compared with GD occurring in the patients without CHC.

Adrenocorticotropin/cortisol and arginine-vasopressin secretory patterns in response to ghrelin in normal men.

This study was performed in order to establish the secretory patterns and the possible relationships between the adrenocorticotropin (ACTH)/cortisol and arginine vasopressin (AVP) responses in normal men to the systemic administration of ghrelin, an endogenous ligand for the growth hormone secretagogue receptor. For this purpose, a bolus of 1 microg/kg ghrelin was injected intravenously in 9 normal men. AVP, ACTH and cortisol significantly rose in response to ghrelin injection; however, in all subjects the AVP rise preceded the ACTH/cortisol responses. In fact, the mean peak levels of AVP, ACTH and cortisol after ghrelin injection were observed at 15, 30 and 45 min, respectively. When peak AVP responses to ghrelin were considered together with ACTH and cortisol peak levels, highly significant positive correlations were observed (AVP and ACTH, r = 0.94, p < 0.001; AVP and cortisol, r = 0.92, p < 0.001). In conclusion, this study shows that the AVP response to ghrelin precedes the concomitant ACTH/cortisol rise and that these hormonal responses are highly positively correlated. These observations support the hypothesis that AVP mediates ghrelin-induced ACTH secretion in normal men.

Is steroid therapy needed in the treatment of destructive thyrotoxicosis induced by alpha-interferon in chronic hepatitis C?

OBJECTIVE: Treatment with interferon (IFN) of patients affected by chronic hepatitis C (CH-C) may produce alterations in thyroid function, such as hypothyroidism, Graves'-like hyperthyroidism and destructive thyrotoxicosis (DT). IFN-induced DT is characterized by suppressed serum TSH levels, normal or elevated FT4 and FT3 concentrations, with the presence or absence of thyroid peroxidase antibodies and antithyroglobulin antibodies, the absence of thyroid receptor antibodies and radioactive iodine uptake suppressed or <5%. DESIGN: IFN-induced DT is a mild clinical disease, because thyroid-destructive processes last for a short time and involve a small portion of the gland. At present, the therapeutic approach in DT suggests IFN withdrawal and 1-2 months of methylprednisolone treatment. METHODS: In consideration of possible untoward side effects of steroid treatment in patients with CH-C, we studied two groups of patients with CH-C who developed DT after treatments with various preparations of recombinant IFN (with or without ribavirin). Patients sequentially entered the study during a 4-year period, at the time of DT diagnosis, when IFN therapy was discontinued. The first 12 subjects (group A) were treated with 8-16 mg/day methylprednisolone for 30-40 days after IFN withdrawal; in the following 15 patients (group B), IFN withdrawal was not followed by any additional treatment. All patients underwent clinical and laboratory controls of thyroid function at 1, 2, 3 and 6 months after DT diagnosis. RESULTS: The results showed restoration of euthyroidism in both group A and group B patients at 6 months after DT diagnosis, regardless of steroid treatment. CONCLUSIONS: The simple withdrawal of IFN therapy in patients with CH-C, who had developed DT, appears to be effective in the treatment of the thyroid disease. This therapeutic approach should be preferred in order to avoid possible undesired side effects of steroid therapy in patients with CH-C.